Both IL-4 and IL-13 are therapeutically important cytokines based on their biological functions and play critical roles in many diseases, including asthma (Curr Opin Allergy Clin Immunol 2005, Vo. 5, 161-166). IL-4 has been shown to be able to inhibit autoimmune disease, and IL-4 and IL-13 have both shown the potential to enhance anti-tumor immune responses. Since both cytokines are involved in the pathogenesis of allergic diseases, inhibitors of these cytokines could provide therapeutic benefits.
In order to develop a pharmaceutical formulation containing an anti-IL-4/anti-IL-13 bispecific antibody suitable for subcutaneous administration, the antibody must be concentrated to about 100 mg/mL or greater. However, many complications can arise at such high concentrations, including an increase in viscosity, a shift of pH, a change in the color of the solution, and the formation of visible and sub-visible particles. Formulation of the antibody is further complicated by the fact that it is highly prone to aggregation at high concentrations. While typical antibodies normally form high molecular weight aggregates (HMW) below 5% over a time period of 4 years at 5° C., the anti-IL-4/anti-IL-13 bispecific antibody forms HMW at a rate of between 0.5-1% per hour at 25° C., and at 0.1% per hour at 5° C. Indeed, this antibody has such a strong propensity to aggregate that it cannot be formulated in a liquid in the concentration range targeted. Finally, the anti-IL4/anti-IL13 bispecific antibody has a particularly low isoelectric point, making it more difficult to formulate due to solubility issues. For example, the anti-IL4/anti-IL13 bispecific antibody has an isoelectric point between 5.8 and 6.2, whereas most antibodies have an isoelectric point between 8 and 10.
Accordingly, a need exists for improved and stable pharmaceutical formulations that can address these complications.